Infections with viruses, and rhinoviruses in particular, are major causes of asthma exacerbations, and[unreadable] account for a large percentage of the morbidity and economic costs associated with asthma. Current[unreadable] asthma treatment, although effective in the control of allergic asthma, is not always capable of preventing[unreadable] exacerbations of wheezing due to respiratory infections. Based on this unmet clinical need, we propose a[unreadable] program of multifaceted and highly interactive studies to establish the mechanisms by which RV cause[unreadable] exacerbations of asthma. The severity of viral infections and their effects on the lower airway are dependent[unreadable] on factors related to the virus and the host. Our overall hypothesis is that the severity of RV infections[unreadable] and resulting airway dysfunction is critically dependent on a) the interplay between RV replication in[unreadable] the epithelial cell and early innate antiviral responses, and b) variations in the host regulation of proinflammatory[unreadable] and antiviral responses to infection. Our previous work has focused primarily on the ability[unreadable] of RV to infect the lower airway, upregulate inflammation and thereby initate lower airway obstruction and[unreadable] symptoms. The differential nature of these responses may well determine why certain individuals have[unreadable] significant exacerbations of asthma with virus infections, while others simply have clinical "colds." We now[unreadable] propose five interactive and innovative projects that involve mechanistic studies in isolated populations of[unreadable] cells, and in vivo models in both the human and the mouse. The in vitro projects include experiments to[unreadable] define virus-induced mechanisms of macrophage priming (Project by Bertics), recruitment and activation of[unreadable] neutrophils into the airway (Project by Huttenlocher), and the destruction of epithelial cell nuclear pores to divert cellular[unreadable] metabolism towards viral protein synthesis and replication (Project by Palmenberg). These in vitro studies are[unreadable] complemented by two in vivo models: a genetics study to identify associations with clinical and biologic[unreadable] outcomes of experimentally-induced RV infection (Project by Gern), and a murine model of picornavirus[unreadable] (mengovirus) infection to evaluate mechanisms of virus-induced cellular inflammation. These projects'[unreadable] approach to identify critical host/virus interactions that determine the severity of illness and respiratory[unreadable] dysfunction are synergistic, interactive, and take advantage of a unique set of resources and decades of[unreadable] published experience in this area found at the University of Wisconsin. Collectively, these will studies[unreadable] address clinically relevant gaps in our current understanding of virus-induced airway dysfunction and[unreadable] facilitate the development of new and more efficacious therapeutic strategies.[unreadable] Lav Summary: Infections with rhinovirus, a common cold virus, are the major cause of asthma[unreadable] exacerbations in children, and continue to be a problem for adults with asthma. The goal of this project is to[unreadable] determine why this is so, and identify new approaches to either prevent or treat rhinovirus-induced asthma.